VALTOCO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for VALTOCO (VALTOCO).
GABA-A receptor positive allosteric modulator; increases chloride ion conductance, hyperpolarizes neurons, and suppresses seizure activity.
| Metabolism | Hepatic via CYP3A4 and CYP2C9; active metabolite desmethyldiazepam (nordazepam) |
| Excretion | Renal (70% as unchanged drug and metabolites, primarily glucuronide conjugate, with <2% as unchanged drug); biliary/fecal (30%) |
| Half-life | Terminal elimination half-life: 15-17 hours (range 11-20 h) in adults; no dose adjustment for age or renal impairment is recommended, but clinical monitoring is prudent in hepatic impairment. |
| Protein binding | 96% bound, primarily to albumin |
| Volume of Distribution | 0.5-0.8 L/kg; approximates total body water, indicating extensive tissue distribution. |
| Bioavailability | Intranasal: 75% (range 65-85%) relative to intravenous; rectal: 70-90% relative to intravenous. |
| Onset of Action | Intravenous: rapid (minutes) for seizure cessation; intranasal: 2-5 minutes for seizure termination in status epilepticus based on clinical trials. |
| Duration of Action | 4-6 hours for seizure control; may require repeated dosing or alternative therapy if seizure persists beyond 5 minutes. |
| Molecular Weight | 284.7 |
5 mg, 10 mg, 15 mg, or 20 mg intranasally as a single dose based on weight; for patients weighing <50 kg: 5 mg, 10 mg for 50-75 kg, 15 mg for 75-100 kg, 20 mg for >100 kg. In adults, maximum dose is 20 mg per seizure cluster.
| Dosage form | SPRAY |
| Renal impairment | No dosage adjustment required for mild to moderate renal impairment. Severe renal impairment (eGFR <15 mL/min): consider using lower doses due to increased exposure; use with caution. |
| Liver impairment | Child-Pugh A or B: no adjustment needed. Child-Pugh C: reduce dose by 50% due to increased diazepam exposure. |
| Pediatric use | Age 6-17 years: 0.2 mg/kg intranasally, maximum single dose 20 mg. Administer as single dose per seizure cluster. Not recommended for children <6 years. |
| Geriatric use | Elderly patients may have increased sensitivity; consider starting at lower end of dosing range (5-10 mg) and titrate based on response and tolerability. Use with caution due to risk of sedation and falls. |
| 1st trimester | Valtoco (diazepam) is generally avoided during the first trimester due to increased risk of congenital malformations, particularly cleft lip/palate, based on some epidemiological studies. Use only if clearly needed and benefit outweighs risk. |
| 2nd trimester | Use with caution; potential risks include low birth weight and preterm birth. Maternal sedation and neonatal withdrawal may occur. |
| 3rd trimester | Use near delivery may cause neonatal respiratory depression, hypotonia, feeding difficulties, and withdrawal symptoms (floppy infant syndrome). Avoid chronic use or high doses. |
Clinical note
Comprehensive clinical and safety monograph for VALTOCO (VALTOCO).
| Placental transfer | Diazepam readily crosses the placenta, with fetal plasma concentrations approximately equal to maternal concentrations after intravenous administration. Extensive placental transfer occurs. |
| Breastfeeding | Diazepam and its active metabolite (nordiazepam) are excreted into breast milk in low amounts. However, due to long half-life and accumulation in neonates, especially with repeated doses, breastfeeding is generally not recommended during chronic use. Occasional single doses are likely compatible, but monitor infant for sedation and poor feeding. |
■ FDA Black Box Warning
WARNING: RISK OF RESPIRATORY DEPRESSION AND CARDIAC ARREST WITH CONCOMITANT USE OF ALCOHOL OR OTHER CNS DEPRESSANTS; RISK OF SUBSTANCE ABUSE, DEPENDENCE, AND WITHDRAWAL; WITHDRAWAL SEIZURES; AND RISK OF SERIOUS SKIN REACTIONS.
| Serious Effects |
Severe respiratory insufficiencySevere hepatic insufficiency (hepatic encephalopathy)Myasthenia gravisAcute narrow-angle glaucomaKnown hypersensitivity to diazepam or benzodiazepines
| Precautions | Risk of CNS depression and impaired motor function, Risk of abuse and dependence, Risk of withdrawal seizures upon abrupt discontinuation, Risk of serious skin reactions (e.g., Stevens-Johnson syndrome), Concomitant use with opioids may cause profound sedation, respiratory depression, coma, and death, Use in patients with compromised respiratory function or hepatic impairment requires caution |
| Food/Dietary | No specific food interactions. Avoid alcohol consumption during VALTOCO use as it may increase CNS depressant effects. |
Loading safety data…
| Lactation Rating | L3 (Moderately Safe) - Use caution; benefit should outweigh risk. |
| Teratogenic Risk | Diazepam (active moiety in VALTOCO) is Pregnancy Category D. First trimester: Associated with increased risk of congenital malformations, particularly cleft lip/palate, when used chronically. Second and third trimesters: May cause fetal benzodiazepine exposure leading to floppy infant syndrome, neonatal withdrawal, and central nervous system depression. Late third trimester or delivery: Risk of neonatal respiratory depression, hypotonia, and feeding difficulties. |
| Fetal Monitoring | Monitor maternal: vital signs, respiratory rate, sedation level, and seizure activity. Fetal/neonatal: Fetal heart rate monitoring during seizure management; after delivery, observe neonate for respiratory depression, hypotonia, withdrawal symptoms (tremors, irritability), and sedation. Consider umbilical cord blood drug levels if exposure near delivery. |
| Fertility Effects | No direct fertility effects reported. Benzodiazepines may affect libido or menstrual cycles in women. No significant impact on male or female fertility in animal studies. Long-term use may be associated with hormonal disturbances. |
| Clinical Pearls | VALTOCO (diazepam nasal spray) is indicated for acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) in patients with epilepsy aged 6 years and older. Administer one spray into one nostril; if needed, a second spray into the opposite nostril can be given after 4 hours if seizure activity persists. Do not use more than two doses per episode. Onset of action is rapid (within 2-5 minutes). Monitor for respiratory depression, especially in patients with compromised respiratory function or concomitant CNS depressants. Each spray delivers 5 mg or 10 mg diazepam; the dose depends on patient weight (5 mg for <40 kg, 10 mg for ≥40 kg). Tilt patient's head back slightly during administration. Do not reuse the device; discard after use. |
| Patient Advice | Use VALTOCO exactly as prescribed; only for seizure clusters, not for daily seizures. · Administer one spray into one nostril; do not prime the device. · After administration, tilt head back slightly and breathe normally. · If seizure activity continues after 4 hours, a second dose may be given in the opposite nostril. · Do not use more than two doses per seizure episode; if ineffective, seek emergency medical help. · Store at room temperature (20-25°C); protect from light and moisture. · Keep out of reach of children; discard device after use. · May cause dizziness, drowsiness, or coordination problems; avoid driving or operating machinery until effects wear off. · Inform healthcare provider of all medications, especially CNS depressants (e.g., alcohol, opioids, sedatives). · Do not consume alcohol while using VALTOCO. |